Biological Sciences Research Highlights

For Robust SLIM, an R&D 'Oscar'

Yehia Ibrahim represented the SLIM team at the R&D 100 Awards ceremony.

Disruptive technologies change the way we live.

Think of cell phones, personal computers, email, and the telephone, which in 1876 Alexander Graham Bell called his "harmonic telegraph."

Richard D. Smith, a Battelle Fellow at the Pacific Northwest National Laboratory (PNNL), invites you to consider another entry into this rare realm of culture-shaking innovations.

Structures for Lossless Ion Manipulations (SLIM) is a new, fast, robust technology for doing things with molecules. Smith said one of its potentially most important applications will open new avenues for analytical measurements—extending them to the level of a single cell, and doing them 1,000 times faster and with more sensitively than present technologies.

SLIM will help personalize medicine, sharpen drug discovery and testing, and has the potential to make waves beyond medicine, in the realms of clean energy and environmental management.

Thanks to SLIM, said Smith, in the near future your doctor’s office will likely include a tabletop instrument that rapidly analyzes blood, tissue, and urine—and do it better than large and expensive laboratory instrumentation does today. It will sort and measure molecules, searching for those telltale components that predict or indicate states of disease or health.

The device will save lives and time by tracking the progress of tumors, monitoring biomarkers, and by rapidly detecting and accurately diagnosing diseases.

SLIM is disruptive, he said, not only because it is compact and affordable, but also because it can make measurements of molecules in samples that are now very difficult or completely impractical.

Consider also SLIM’s groundbreaking analytical speed and sensitivity. It’s capable of analyses orders of magnitude faster than the current technologies commonly used to distinguish the presence, structure, and abundance of different molecules in a sample.

In a clinical setting it is believed that these capabilities will help usher in an era of personalized medicine, in part by broadly monitoring health as well as providing early disease detection for individual patients.

Big, Bigger, SLIM

What makes SLIM so big?

In the realm of medicine at least, the answer is disruption. SLIM is likely to disrupt well-established but cumbersome technologies used to identify biomarkers, proteins, and other components in blood and tissue samples.

Advances in medicine (as well as in clean energy and environmental management) require the ability to distinguish—that is, separate and identify—different metabolite or protein molecules in a biological sample. To most scientific instruments, however, many molecules often look the same, and can have exactly the same mass.
Yet even slightly different arrangements of atoms can impact biological function as well as spur toxicity. With a slight molecular twist at the atomic level, a drug can become a poison. (In their R&D 100 application, Smith and others told the cautionary tale of thalidomide. The morning sickness drug caused profound birth defects when manufactured with an impurity having just a slightly different molecular structure.)
Another problem is that often there are too few molecules in a sample to detect. Having the sensitivity needed to detect these molecules in these analyses is crucial. After all, many important biomarkers are present only at very, very low concentrations.

Answering Present Challenges

To identify a molecule's structure and function, scientists have to separate and detect the different molecules in a sample so they can identify every component and how much of each is present. Conventionally, they use liquid chromatography to first separate compounds from a sample in a liquid. Then they make ions from the molecules as samples are transferred to the gas phase, where the rest of the analysis takes place.

The current standard technology for analyzing molecules is based on the most advanced forms of mass spectrometry (MS), which are only found only in large laboratories, and which are slow and expensive.

MS also often lacks two other important qualities: enough sensitivity to detect many important components, and the ability to distinguish different molecules in a sample that have the same mass but different structures. Moreover, some ions are lost during analysis because compounds make contact with surfaces. That means not all parts of a sample reach the MS stage.

Coupling MS with other conventional separation approaches (such as liquid chromatography) takes many hours for the analysis. These conventional technologies also have problems with the resolution of a separation, which is critical to a researcher’s ability to distinguish and identity a sample’s various components. This is because the resolution of ion separations depends on the length of the ion-measurement drift path, which in conventional devices is limited to "about 3 feet," said Smith.

Adding extra length (while remaining compact) is one of the ways SLIM dramatically changes the game. Instead of being limited to a 3-foot linear path, SLIM allows ions to follow serpentine pathways. It makes much longer paths possible—along with second or third (or even more) laps of the same path to achieve greater separation. Currently, SLIM provides over 40 feet of pathway in a device only about a foot long, a foot wide, and half an inch thick.

As ions turn at 90-degree angles and race along these charged pathways, they separate into groups by size—even if the size differences are tiny.

Turning Corners

One key to the SLIM breakthrough was addressing the question: How can we turn ions around a corner, in a way that does not destroy a separation?

Another key was the SLIM design itself. It packed so much drift pathway into such a small space that SLIM made previously impractical approaches highly practical.

"Once you turn ions around a corner, then you can turn them around two corners, three corners," said Yehia M. Ibrahim, a senior scientist and a co-inventor and developer of SLIM at PNNL. "SLIM then allowed us to build long serpentine paths that could provide extremely long lengths—15, 20, 30, 60 meters and more—in a small device."

SLIM propels the ions along the pathways using what are called traveling wave electric fields, which make very long paths possible without the need to increase voltages as the paths lengthen. Meanwhile, the electric fields also prevent ions from ever touching the surfaces, so none are lost during analysis. (Hence, SLIM is a "lossless" system for ion manipulation.)

Because of its long separation paths compared to conventional technologies, SLIM can better separate, group, and analyze molecules—even ones very close in size and structure. It is this ability to finely distinguish among different compounds in a biological sample that is central to the tabletop analysis device now being developed at PNNL.

SLIM holds promise in the realms of personalized medicine, as well as in chemical analytics, therapeutic drug monitoring, and improved immunoassays. It could also enhance drug discovery in at least three ways: by detecting molecules that affect toxicity, by identifying therapeutic targets, and by enabling research on metabolic pathways.

What's Next

The potential is even greater, said Smith. SLIM could be the basis for a range of chemistry applications where ions are reacted to create new compounds; where products are purified; or where new materials and catalysts are produced.

In essence, SLIM will provide what Smith refers to as a "gas-phase ion chemistry workbench." It will allow a whole new universe of compounds and materials to be synthesized, purified, and collected, he said, "with future impacts we can now only guess at."